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Abstract

Acute aortic dissection (AAD) is a common disease with sudden onset and high mortality, for which pathogenesis is largely unknown. To better understand AAD pathogenesis, we examined three mouse models of AAD; knockout mice for tenascin C, an extracellular glycoprotein that is secreted by vascular smooth muscle cells (VSMCs), macrophage-specific knockout of SOCS3 (mSOCS3-KO), a negative regulator of JAK/STAT signaling, and infusion of beta-aminopropionitrile, that blocks crosslinking of elastin and collagens. All of three models develop AAD upon the continuous infusion of angiotensin II (AngII). We performed transcriptome analyses at the early time point of AngII infusion when the aortic structure showed no obvious abnormality. Interestingly, the gene expression patterns showed common changes; induction of proinflammatory molecules and cell cycle machinery, and suppression of the structural extracellular matrix (ECM) and cytoskeletal molecules of VSMCs. Such a pattern is consistent with that in human AAD as previously reported. We performed detailed analysis in mSOCS3-KO. Bayesian network model revealed that upregulation of cell cycle machinery precedes other changes in the gene expression. Cell cycle analyses using Ki67 staining and BrdU uptake assay showed that AngII caused proliferative response before AAD development both in macrophages and in VSMCs, indicating the macrophage-VSMC interaction. In addition, the proliferative response of macrophages was associated with the preferential differentiation into the proinflammatory M1 phenotype as determined by the high expression of Ly6C. Our findings showed a gene expression network of AAD that is common to human and mouse models. The findings in mouse models suggest that cell cycle activation precedes both the proinflammatory response in macrophages and the functional deterioration of VSMCs, which in turn would weaken the aortic wall strength. In addition, tissue-specific knockout studies revealed that interactions between macrophages and VSMCs underlie the gene expression network in AAD. Deciphering such cellular interactions and gene expressions would lead to better understanding of this fatal disease.